Development of better drug delivery systems based on DNA nanostructures

Significance 

DNA nanotechnology which is the research field using DNA molecules as building material has developed rapidly during recent years and enabled the construction of increasingly complex nanostructures. DNA nanostructures, such as DNA origami, serve as an excellent foundation for nanocarrier-based drug delivery applications, and examples of their use in medical treatments have already been demonstrated. Although the stability of such DNA nanostructures under physiological conditions can be improved, little is known about their digestion by endonucleases, which, found everywhere in our blood and tissues, are responsible for destroying foreign DNA in our bodies.

To tackle this emerging question, a team of researchers from Aalto University (Finland), the University of Jyväskylä (Finland), Ludwig-Maximilian-Universität München (Germany) and Universität Paderborn (Germany) have found a way to study the endonuclease-driven digestion of drug-loaded DNA nanostructures in real time.

The researchers’ previous experiments used high-speed atomic force microscopy to show that the design of DNA origami plays a role in how quickly they break apart in an endonuclease-rich environment. While they could follow the digestion process at a single-structure level, the approach was limited to two-dimensional DNA origami shapes deposited on a microscope substrate.

Now the group has monitored DNA degradation and the subsequent anti-cancer drug doxorubicin (Dox) release from the DNA structures. The drug bonds between DNA base pairs.

They observed both the digestion and drug release profiles as the drug is released upon DNA fragmentation by nucleases, and importantly, in the solution phase. With this method we can actually see the collective behavior of all the nanostructures when they are floating freely in liquid

It seems the digestion happens differently on substrates and in solution, and by combining these two types of information, we can better understand how the nanostructures are digested by nucleases in the bloodstream. Moreover, we showed that the drug release profiles were closely linked to the digestion profiles, and a wide range of drug doses could be achieved simply by changing the shape or geometry of the DNA nanostructure.

As the team investigated the binding of Dox to the DNA structures in great detail, they discovered that the majority of previous studies have vastly overestimated the Dox loading capacity of DNA origami.

The anti-cancer effects of Dox-equipped DNA nanostructures have been reported in many publications, but it seems these effects may have been mainly caused by free or aggregated Dox molecules, not by the drug-loaded DNA motifs. We believe this type of information is crucial for the development of safe and more effective drug delivery systems, and brings us one step closer to real-world DNA-based biomedical applications.

The research team findings underline the significant potential of DNA origami nanostructures in drug delivery applications and provide guidelines for choosing appropriate protocols for preparing, studying, purifying and storing DOX-loaded DNA origami nanostructures.  They believe their study will help in building a solid ground for the development of safe and more efficient DNA nanostructure-based therapeutics with promising programmable features.

Development of better drug delivery systems based on DNA-carriers - Medicine Innovates
Anti-cancer Dox molecules (red) are loaded into DNA origami nanostructures (blue bow tie) through intercalation. 2) DNA origami is digested by endonuclease (green). 3) As the origami is broken down into short single-stranded fragments, the Dox is released into the surrounding environment. Credit: Aalto University

About the author

Prof. Dr. Tim Liedl is Professor for experimental physics at the Ludwig-Maximilians Universität since 2009.

He received his diploma in physics in 2004 in the group of Wolfgang J. Parak at Ludwig-Maximlians-University Munich (LMU) where he worked on the development of hydrophilic coatings for fluorescent semiconductor nanoparticles. In 2007 he obtained his Ph.D. in the group of Friedrich C. Simmel studying DNA-based nanodevices and switches which are driven by chemical oscillations. From spring 2007 till summer 2009 he visited William M. Shih’s laboratory at Dana-Farber Cancer Institute / Harvard Medical School where he used the DNA-origami method to construct self-assembling two- and three-dimensional structures.

The research of Tim Liedl is multi-disciplinary and exploratory positioned at the interface between nanoscience, synthetic biology and cell-biology. Its current focus lies on the application of DNA-based nanostructures in biology and on self-assembled plasmonic materials.

Reference

Heini Ijäs, Boxuan Shen, Amelie Heuer-Jungemann, Adrian Keller, Mauri A Kostiainen, Tim Liedl, Janne A Ihalainen, Veikko Linko. Unraveling the interaction between doxorubicin and DNA origami nanostructures for customizable chemotherapeutic drug release. Nucleic Acids Research, 

Go To Nucleic Acids Research

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